Immune-mediated inflammatory diseases, or IMIDs, is another term, which is used to describe immune-mediated diseases associated with inflammatory pathogenesis mechanisms. IMIDs are characterized by immune dysregulation that results in acute or chronic inflammation, causing organ or tissue damage. One causal manifestation of immune deregulation is the inappropriate expression of proinflammatory cyto-kines, such as IL-1, IL-6 and TNF-a as well as Th1/Th2 cytokine disbalance leading to pathological consequences. This is in agreement with the "cytokine theory of disease," which states that an overproduction of cytokines can cause the clinical manifestations of disease (Nathan 2002; Frieri 2003; Elenkov et al. 2005; Tracey 2005). For instance, Th1-associated IMIDs include rheumatoid arthritis, Crohn's disease, multiple sclerosis, SLE, type I diabetes mellitus, psoriasis, sarcoidosis, an-kylosing spondylitis, uveitis, and pathologic conditions associated with lung transplantation. Th2-associated disorders are asthma and allergies, pulmonary fibrosis, and ulcerative colitis. Diseases related to inappropriate expression of inflammatory cytokine are represented by osteoarthritis, chronic obstructive pulmonary disease (COPD), traumatic brain and spinal cord, and Alzheimer's disease. Furthermore, autoinflammatory diseases can be specified as inborn errors of the innate immune system. The main component of autoinflammatory diseases is the group of hereditary periodic fevers that are characterized by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system, and skin (Grateau 2006). Finally, new diseases are constantly added to the IMID group. For instance, recent data suggest that many risk factors leading to the development of osteoporosis, a major cause of morbidity in older people, could exert their effects through immunologically mediated modulation of bone remodeling. "Inflamm-ageing" plays a role in bone remodeling through proinflammatory cytokines, which are known to influence osteoclasts and osteoblasts (De Martinis et al. 2006). Thus, immune-mediated inflammation may play an important role in determining bone resorption and support the appearance of new discipline, osteoimmunology (Walsh et al. 2006).
Interestingly, an excessive Th1-type proinflammatory response is believed to be a common base for autoimmune disorders, whereas excessive Th2-type cytokine production (IL-4, IL-5, and IL-13) is associated with supporting of IgE and eosinophilic responses and is believed to be the cause of allergic disorders (Singh et al. 1999). An increasing number of scientific publications provide proof for the concept that an impairment of immune-tolerance mechanisms might be causally related to the development of unwanted Th2-driven, allergen-induced airway diseases. Impaired expansion of natural and/or adaptive Tregs is hypothesized to lead to the development of allergy and asthma (Umetsu and DeKruyff 2006). However, the results of the relationship between Th2-related atopic disorders and Th1-related autoimmune diseases are conflicting. Some epidemiologic studies concluded that Th2-weighted imbalance that favors allergic response, might be protective against Th1-related autoimmune disorders. Indeed, atopic eczema was shown to be associated with a lower risk for type 1 diabetes mellitus in children (Stene and Joner 2004). Similarly, another report demonstrated reduced frequency of allergic symptoms in children with type 1 diabetes (Caffarelli et al. 2004). In contrary, increased incidence of asthma in patients with type 1 diabetes, rheumatoid arthritis, and IBD was also reported (Kero et al. 2001; Simpson, Anderson et al. 2002). These and other findings suggest that the significance and the role of Th1/Th2 paradigm in supporting different immune-mediated diseases might be oversimplified and should be further investigated (Sheikh et al. 2003).
The link between other major groups of immune-mediated diseases, particularly cancer and allergies, has been discussed for years with a variety of supporting and disproving evidence. Theoretically, two contradictory hypotheses may be advanced: either tumor immunosurveillance may operate more efficiently in those individuals who have allergies or the alterations of the immunologic system can enhance inflammatory response and favor the tumor onset (Carrozzi and Viegi 2005). Many studies suggest that the association between allergy and cancer is complex and depends on the specific allergy and the specific organ site under consideration. For instance, following the cohort of patients for 6 years, Mills et al. reported that prostate and breast cancer risk were elevated in persons who reported any type of allergic history, as was risk of lymphatic or hematopoietic cancers and sarcoma. For each of these types of cancer, risk increased with increasing numbers of allergies. However, ovarian cancer risk was decreased in persons with any allergic history, and increasing numbers of allergies was associated with decreasing risk of this form of cancer (Mills et al. 1992). Similarly, evaluating the associations among certain allergic disorders, atopy upon skin-prick testing, and specific cancers in a prospective study, Talbot-Smith et al. reported that having a skin reaction to house dust mites nearly tripled the risk of prostate cancer: however, history of asthma and hay fever was associated with a trend toward a reduced risk of colorectal cancer and increased risk of leukemia, but no association was found between breast and lung cancers and allergic disorders or atopy (Talbot-Smith et al. 2003).
Analyzing available published reports, Wang and Diepgen concluded that despite the mixed results, the emerging picture from most of the currently available epidemiological data indicates that atopic disease is associated with a reduced risk for cancer (Wang and Diepgen 2005). On the other hand, there seems to be a clear association of lung cancer with asthma, and thus, asthmatic subjects have to be considered "at risk" for lung cancer (Carrozzi and Viegi 2005). But, the result of another examination reveals that there is significant lower frequency of allergic diseases in patients with lung cancer in comparison with frequency of allergic diseases in control adult population (Tolak et al. 2006). Another study demonstrated a reduced risk of primary malignant brain tumors in people reporting asthma, hay fever, and other allergic conditions (Schwartzbaum et al. 2005). In contrast to most previous studies, Soderberg et al. (2004) study suggests that allergic conditions might increase the risk of some hematological malignancies. The study showed that people with hives and asthma were about twice as likely to develop leukemia and those who had eczema are under an increased risk of non-Hodgkin's lymphoma. At the same time, a possible connection between allergy and cancer has been suspected, but allergy-related conditions or atopy have been inconsistently associated with reduced risks of non-Hodgkin lymphoma, suggesting that allergy may not be causally associated with the risk of non-Hodgkin lymphoma (Melbye et al. 2007). Thus, the problem of whether allergy is a "risk" or a "protective" factor for cancer is far to be solved.
Another recent report suggests that autoimmunity and malignancy frequently coexist and they may share etiological and pathological mechanisms (Toubi and Shoenfeld 2007). For instance, natural protective autoantibodies against tumorantigens were isolated from patients and healthy donors reflecting the development of naturally occurring B cell responses during the process of cancer evolvement. They fulfill the definition of autoantibodies since they are self-reactive, and they also bind altered self-antigens such as tumor cells. In this regard, various autoantibodies such as anti-dsDNA and anti-Fas autoantibodies were found to be significantly higher in patients with various carcinomas, thus playing a role for their improved survival. Finally, clinical use of a number of biologic response modifiers including cytokines, antibodies, and other immunomodulators might be associated with an increased risk of malignancy during the treatment of allergic or autoimmune diseases and vice versa (Kong et al. 2006).
In spite of the controversy of positive and negative relationships between incidences of certain immune-mediated diseases, it is clear that there are both etiopatho-genetic and clinical consequence links between many of these disorders. For instance, certain immune-mediated diseases, such as type 1 diabetes or arthritis, are not just very common but result in more than 19,000 organ-transplant recipients each year in the United States. Even though the first reference to the concept of organ transplantation and replacement for therapeutic purposes may be dated to approximately 200 AD, when Hua-To in China replaced diseased organs with healthy ones, only in 1954, the kidney was the first human organ to be transplanted successfully. Liver, heart, and pancreas transplants were successfully performed by the late 1960s, while lung and intestinal organ-transplant procedures were begun in the 1980s. Increasing numbers of transplants in patients with immune-mediated diseases, such as autoimmune and malignant diseases, was responsible for a new group of immunemediated diseases, that is, diseases associated with organ, tissue, or cell transplantation, for example, graft-versus-host disease or graft rejection. On the other hand, transplantation is the leading form of treatment for many forms of end-stage organ failure and has saved and enhanced the lives of more than 300,000 people in the United States. With this success, however, has come increasing demand for donated organs. Today, approximately 85,000 people are awaiting transplants nationwide with almost 50,000 people awaiting kidney transplant. Sadly, approximately 17 patients die every day while waiting for organ for transplantation, that is, one person every 85 min. More than 10,000 people are on the Eurotransplant waiting list in a similar situation.
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